Peribañez-Dominguez Sara, Parra-Guillen Zinnia, Troconiz Iñaki F
Department of Pharmaceutical Science, School of Pharmacy and Nutrition, University of Navarra, 31009 Pamplona, Spain.
Navarra Institute for Health Research (IdiSNA), 31002 Pamplona, Spain.
Pharmaceutics. 2025 Jan 3;17(1):57. doi: 10.3390/pharmaceutics17010057.
BACKGROUND/OBJECTIVES: Colorectal cancer (CRC) holds the third and second position among cancers affecting men and women, respectively. Frequently, the first-line treatment for metastatic CRC consists of the intravenous administration of 5-fluorouracil and leucovorin in combination with oxaliplatin or irinotecan. Physiologically-based pharmacokinetic models (PBPK) aim to mechanistically incorporate body physiology and drug physicochemical attributes, enabling the description of both systemic and organ drug exposure based on the treatment specificities. This bottom-up approach represents an opportunity to personalize treatment and minimize the therapeutic risk/benefit ratio through the understanding of drug distribution within colorectal tissue. This project has the goal of characterizing the systemic and tissue exposure of four anti-cancer drugs in humans using a PBPK platform fed with data from the literature.
A literature search was performed to collect clinical data on systemic concentration versus time profiles. Physicochemical features were obtained from the literature, as well as parameters associated with distribution, metabolism, and excretion. The PBPK models were built using PK-Sim.
The data from 51 clinical studies were extracted and combined in one single dataset. The PBPK models successfully described the exposure vs. time profiles with respect to both, with both the typical tendency and dispersion shown by the data. The percentage of observations falling within the two-fold error bounds ranged between 94 and 100%. The colon/plasma AUC ratios were similar for 5-FU, oxaliplatin, and leucovorin, but it was significantly higher for irinotecan.
The PBPK models support tailored treatment approaches by linking in vitro studies to organ exposure. These models serve as the initial step towards incorporating a dedicated tumor compartment, which will further account for the variability in tumor microenvironment characteristics to improve therapeutic strategies.
背景/目的：结直肠癌（CRC）在影响男性和女性的癌症中分别位居第三和第二。通常，转移性CRC的一线治疗包括静脉注射5-氟尿嘧啶和亚叶酸，联合奥沙利铂或伊立替康。基于生理的药代动力学模型（PBPK）旨在从机制上纳入身体生理学和药物理化特性，从而能够根据治疗特异性描述全身和器官的药物暴露情况。这种自下而上的方法为个性化治疗提供了契机，并通过了解药物在结直肠组织内的分布来最小化治疗风险/获益比。本项目旨在利用一个基于文献数据的PBPK平台，描述四种抗癌药物在人体中的全身和组织暴露情况。
进行文献检索以收集关于全身浓度随时间变化曲线的临床数据。从文献中获取理化特征以及与分布、代谢和排泄相关的参数。使用PK-Sim构建PBPK模型。
从51项临床研究中提取数据并合并到一个单一数据集中。PBPK模型成功地描述了两种药物的暴露量随时间变化的曲线，呈现出数据的典型趋势和离散度。落在两倍误差范围内的观察值百分比在94%至100%之间。5-氟尿嘧啶、奥沙利铂和亚叶酸的结肠/血浆AUC比值相似，但伊立替康的该比值显著更高。
PBPK模型通过将体外研究与器官暴露联系起来，支持个性化治疗方法。这些模型是纳入专用肿瘤区室的第一步，这将进一步考虑肿瘤微环境特征的变异性，以改进治疗策略。
